ABSTRACT Despite effective anti-retroviral therapy (cART), HIV-infected individuals remain at an unusually high risk of morbidity and mortality from HIV-associated non-AIDS (HANA) clinical conditions, such as cardiovascular disease,neurocognitivedecline,andosteoporosis.Theexcessriskfortheseage-relateddiseasesisattributed totheresidualimmuneactivationthatpersistsdespitecART.OldercART-suppressedHIV-infectedindividuals have an even greater risk for these inflammation-driven diseases compared to younger counterparts;? this suggests a synergistic adverse effect of HIV and advanced age. In our preliminary studies, we observed that cART-suppressed HIV+ individuals, especially those of older age (?50), exhibited higher monocyte/macrophage activation and had greater cell-associated RNA levels (ca-RNA) despite no significant difference in reservoir size (HIV DNA), suggesting a link between HIV gene expression and monocyte activation.Importantly,wefoundthatdenovoHIVunsplicedviralRNAexpressionalone,evenintheabsence of virus particle production, can induce production of type I IFN responses and pro-inflammatory cytokines in macrophages. In addition, we observed that HIV and aging appear to synergistically advance CD8+ T cell exhaustion, as defined by increased expression of inhibitory receptors (IRs). Also, co-culture of HIV-infected macrophages and CD8+ T cells revealed that increased IR expression is mediated, at least in part, by type I IFNs. Collectively, these preliminary findings support our central hypothesis that the increased HIV unspliced RNAexpressioninagedindividualsdrivestypeIIFNresponsesfrominfectedmonocytes/macrophages,which in turn promotes CD8+ T cell exhaustion, causing a loss of virological control, and hence, perpetuating this HANA-inducing inflammatory cycle. In this study, we propose innovative approaches and sampling from a prospectivecohortofHIV-infectedindividualsstratifiedbyageandmatchedbydurationofcARTcomparedto age-matched uninfected individuals to test our hypothesis. In Aim 1 we will determine if expression of unsplicedHIVRNAinmacrophagesandageingsynergisticallyenhancetypeIIFNresponses.InAim2wewill determine how age, HIV, and monocyte/macrophage-derived inflammatory responses drive CD8+ T cell exhaustion. In Aim 3 we will evaluate how age and CD8+ T cell exhaustion contribute to the persistence and expression of the viral reservoir. We predict that these studies will lead to the identification of the biological mechanisms that drive HANA diseases despite effective cART. Such insight will be critically important for development of effective strategies to decrease or reverse the persistent immune activation driving disease pathogenesisinthegrowingpopulationofolder(?50yearsold)individualslivingwithHIV.